1. Field of the Invention
This invention relates of the use of a certain thiazolidine-2,4-dione, namely, d1-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dio ne, of the formula ##STR1## or a pharmaceutically acceptable cationic salt thereof, for retarding the development of arterial disease in mammals. More specifically, it relates to a method for reducing the serum cholesterol levels in mammals by administering to said mammals a compound of formula I or a pharmaceutically acceptable cationic salt thereof.
2. General Background
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease has been described in detail by Ross and Glomset in New England Journal of Medicine 295, 369-377 (1976). The earliest stage in this sequence is the formation of "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Cholesterol and cholesteryl ester account for most of this lipid. Further, it is postulated that most of the cholesterol found within the fatty streaks results from uptake from the plasma. These fatty streaks, in turn, give rise to development of the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "complicated lesion" which accounts for the the arterial occlusion and tendency toward mural thrombosis and arterial muscular spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at high risk for development or progression of CVD because of this factor. Individuals who possess independent risk factors in addition to hyperlipidemia are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
The first step in recommended therapeutic regimens for hyperlipidemia is dietary intervention. While diet alone produces adequate response in some individuals, many others remain at high risk and must be treated further by pharmacological means. New drugs for the treatment of hyperlipidemia are, therefore, of great potential benefit for large numbers of individuals at high risk of developing CVD. Further, successful treatment of both the hyperlipidemia and hyperglycemia associated with the diabetic state with a single therapeutic agent is particularly desirable.
The thiazolidine-2,4-dione of formula I above, among others, is disclosed in U.S. Pat. No. 4,703,052 wherein it is taught that such a compound and its pharmaceutically acceptable cationic salts are useful as hypoglycemic agents, capable of lowering blood glucose levels in mammals. That patent also discloses how to prepare such compounds. However, in spite of the above-mentioned use for the thiazolidine-2,4-dione of formula I as a hypoglycemic agent, there was, prior to the time of the present invention, no report of the use or intent to use such a compound or its salts for lowering serum cholesterol levels nor any appreciation of its role in achieving that desirable effect.
Certain 5RS racemic and 5R optically active oxazolidine-2-one compounds of the formula ##STR2## wherein R.sup.b is ##STR3## W is sulfur or oxygen; X and X.sup.1 are each independently H, Cl, F or CF.sub.3 ;
Y is inter alia ##STR4## and certain pharmaceutically acceptable salts thereof are disclosed in international patent application number PCT/US87/01356 which is assigned to and has been filed in the name of the assignee thereof. That patent application also discloses the use of such compounds as hypoglycemic agents and, further, the use of some, if not all, of such compounds to lower blood cholesterol levels.